Metabolic remodeling of dystrophic skeletal muscle reveals biological roles for dystrophin and utrophin in adaptation and plasticity
Loading...
Citations
Altmetric:
Altmetric::
Download
Associated Records
Authors
File Licence
Editors
Date
2021-03-01
Source Title
Molecular Metabolism
Journal Title
Journal ISSN
Volume Title
Publisher
ELSEVIER
Affiliation
Anatomy and Neuroscience
Physiology
Biochemistry and Pharmacology
Medicine (St Vincent's)
Physiology
Biochemistry and Pharmacology
Medicine (St Vincent's)
Document Type
Journal Article
Subject Code
Citation
Hardee, J. P., Martins, K. J. B., Miotto, P. M., Ryall, J. G., Gehrig, S. M., Reljic, B., Naim, T., Chung, J. D., Trieu, J., Swiderski, K., Philp, A. M., Watt, M. J., Stroud, D. A., Koopman, R., Steinberg, G. R. & Lynch, G. S. (2021). Metabolic remodeling of dystrophic skeletal muscle reveals biological roles for dystrophin and utrophin in adaptation and plasticity. Molecular Metabolism, 45, https://doi.org/10.1016/j.molmet.2020.101157.
Access Status
Open Access
Access URL
Open Access URL
Open Access at PMC
Linked Resource URL
NHMRC Grant Code
ARC Grant Code
Description
Abstract
OBJECTIVES: Preferential damage to fast, glycolytic myofibers is common in many muscle-wasting diseases, including Duchenne muscular dystrophy (DMD). Promoting an oxidative phenotype could protect muscles from damage and ameliorate the dystrophic pathology with therapeutic relevance, but developing efficacious strategies requires understanding currently unknown biological roles for dystrophin and utrophin in dystrophic muscle adaptation and plasticity. METHODS: Combining whole transcriptome RNA sequencing and mitochondrial proteomics with assessments of metabolic and contractile function, we investigated the roles of dystrophin and utrophin in fast-to-slow muscle remodeling with low-frequency electrical stimulation (LFS, 10 Hz, 12 h/d, 7 d/wk, 28 d) in mdx (dystrophin null) and dko (dystrophin/utrophin null) mice, two established preclinical models of DMD. RESULTS: Novel biological roles in adaptation were demonstrated by impaired transcriptional activation of estrogen-related receptor alpha-responsive genes supporting oxidative phosphorylation in dystrophic muscles. Further, utrophin expression in dystrophic muscles was required for LFS-induced remodeling of mitochondrial respiratory chain complexes, enhanced fiber respiration, and conferred protection from eccentric contraction-mediated damage. CONCLUSIONS: These findings reveal novel roles for dystrophin and utrophin during LFS-induced metabolic remodeling of dystrophic muscle and highlight the therapeutic potential of LFS to ameliorate the dystrophic pathology and protect from contraction-induced injury with important implications for DMD and related muscle disorders.